LINKER: Learning Interactions between Functional Groups and Residues with Chemical Knowledge‑Enhanced Reasoning and Explainability

Interpretable multilevel interaction modeling for robust protein–protein affinity

MIRAGE provides an interpretable and robust framework for structure-aware prediction, with potential applications in protein engineering and drug design, and explicitly modeling multi-level interactions is important for accurately capturing the determinants of binding affinity.

Native Contact Ratio as a Topological Metric for Machine Learning Based Molecular Docking

Accurate identification of near-native ligand binding poses is a central challenge in structure-based drug design. From a physical point of view, the successful construction of a protein–ligand complex structure is dependent on whether protein and ligand can form enough atomically pairwise interactions that result in a global energy minimum. In this work, we report a machine learning scoring strategy for protein–ligand screening which explicitly considers the Native Contact Ratio (NCR), a topology inspired metric that quantifies the preservation of protein–ligand interfacial contacts as well as interaction energy. This physics-awared supervision strategy provides a simple but efficient gradient field that faithfully reflects the complicated protein energy landscape than conventional 3D coordinate-based objectives. Building on this principle, we present DeepNCR, an energy-informed Transformer framework that encodes approximate Coulombic and dispersive interaction potentials across the protein–ligand binding interface. Furthermore, we introduce a feature pruning step that compresses the interaction tensor from 1470 to 868 dimensions, further improving signal-to-noise ratio and directing model attention toward the interaction motifs critical for binding specificity. The model optimizes topological objectives and at inference drives pose refinement through a differentiable hybrid gradient field integrating predicted NCR and AutoDock Vina energetics. Extensive evaluation on the CASF-2016 benchmark and the 3D-DISCO cross-docking data set demonstrates consistently high performance: a Top-1 docking success rate of 94.7%, a 1% Enrichment Factor of 21.21 in virtual screening, and a Top-1 cross-docking success rate of 34.8%. Mechanistic analysis reveals that NCR-guided optimization enables decoy escaping from local energy minima and drives the recovery of disrupted native interactions, confirming that NCR captures the physical determinants of binding rather than mere geometric proximity.

Structure-conditioned self-supervised learning of residue interaction constraints in protein kinases for variant interpretation

Abstract Motivation Protein kinases are key regulators of cellular signaling and are frequently implicated in human diseases. Although kinase domains are structurally conserved, predicting the effects of amino acid substitutions remains challenging as mutations often introduce subtle structural perturbations that are not captured by sequence-based or evolutionary methods. Existing supervised approaches further rely on pathogenicity annotations that are inconsistent across databases, thereby motivating the development of structure-based, label-independent frameworks for mutation effect prediction. Results We present a structure-based method using SE(3)-transformers to learn residue compatibility with the local structural environment from experimentally resolved kinase 3D structures. Proteins are represented as atom-level graphs with physicochemical descriptors derived from the CHARMM force field and spatial connectivity. The model is trained on two self-supervised tasks given local structural context: masked residue atom reconstruction and masked residue classification. This formulation enables learning of geometric and physicochemical constraints without relying on pathogenicity labels. Evaluation using reconstruction loss, residue prediction accuracy, and comparison with BLOSUM substitution patterns indicate that the model captures biologically meaningful relationships between residue identity and 3D structural context. We interpret the scores assigned to alternative amino acids as measures of structural fitness, where low-scoring residues are hypothesized to be less compatible with the local environment and more likely to induce deleterious effects on protein structure and activity. Availability and implementation https://zenodo.org/records/20393799.

Accurate structural modeling of chemically diverse molecular interfaces with Vilya-2

Vilya-2 is the structure-prediction oracle that de novo peptide design pipelines require--establishing the all-atom approach as a general foundation for the design and evaluation of de novo peptide therapeutics.

Integrating AI-Based Protein Modeling and Fragment Molecular Orbital Analysis for Structure-Based Drug Design.

A Biologically Informed Hybrid Stacking Framework for Protein–Protein Interaction Prediction

Mapping the protein interactome is fundamental to understanding disease mechanisms and facilitating therapeutic development. Although protein language models (PLMs) such as ESM-2 have advanced protein-protein interaction (PPI) prediction, their high-dimensional representations remain difficult to connect to verifiable biological signals. To address this limitation, we propose HybridStack-PPI, a gray-box framework that combines ESM-2 sequence representations with explicit physicochemical and motif-derived biological descriptors. The architecture uses motif-anchored local pooling global mean pooling, symmetric pair encoding, fold-internal feature selection, LightGBM branch learners, and an elastic-net logistic-regression stacking layer. We evaluated the method using a C3 cluster-based cross-validation protocol with a 40% sequence-identity clustering threshold and a Same-GO hard-negative setting in which negative candidates shared functional annotations with positive pairs. Under this setting, HybridStack-PPI reached a Human ROC-AUC of 73.65%, PR-AUC of 91.35%, MCC of 28.06%, and specificity of 75.61%. The results indicate a conservative operating point: compared to more recall-oriented baselines, the proposed stack trades lower recall and F1 for higher specificity, MCC, and ranking behavior under functionally similar negative samples. We further reported cross-species transfer, ablation, latency, SHAP-based descriptor attribution, and meta-learner coefficient analyses to clarify both the promise and limitations of biologically informed PPI prediction.